Radiosurgical Neuromodulation Devices, Systems, and Methods for Treatment of Behavioral Disorders by External Application of Ionizing Radiation

ABSTRACT

Radiosurgical techniques and systems treat behavioral disorders (such as depression, Obsessive-Compulsive Disorder (“OCD”), addiction, hyperphagia, and the like) by directing radiation from outside the patient toward a target tissue within the patient&#39;s brain, typically without imposing surgical trauma. The target will often be included in a neural circuit associated with the behavioral disorder. A cellularly sub-lethal dose of the radiation may be applied and the radiation can mitigate the behavioral disorder, obesity, or the like, by modulating the level of neural activity within the target and in associated tissues. Hypersensitive and/or hyperactive neuronal tissue may be targeted, with the radiation downwardly modulating hyperactive neuronal activity. By down-regulating the activity of a target that normally exerts negative feedback or a limiting effect on a relevant neural circuit, the activity of the circuit may be increased.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a Continuation of U.S. Ser. No. 14/266,090filed Apr. 30, 2014; which application is a Divisional of U.S. Ser. No.13/708,076 filed Dec. 7, 2012 (now U.S. Pat. No. 8,747,292); which is aContinuation of U.S. Ser. No. 12/261,347 filed Oct. 30, 2008 (now U.S.Pat. No. 8,337,382); which claims the benefit of U.S. Provisional Appln.No. 60/984,636 filed Nov. 1, 2007. The full disclosures, all of whichare incorporated herein by reference in their entirety for all purposes.

BACKGROUND OF THE INVENTION

The present invention is generally directed to medical (and in manycases, more specifically to neurological) treatment devices, systems,and methods. In exemplary embodiments, the invention providesradiosurgical treatment methods and systems for directing ionizingradiation toward a target tissue within a brain of a patient so as totreat psychiatric conditions, and particularly to treat behavioraldisorders (such as depression, Obsessive-Compulsive Disorder (“OCD”),addiction, hyperphagia, and the like), and/or to treat obesity. The doseof radiation will often be sub-lethal so that the tissue within thetarget need not undergo frank cell death, with efficacy often insteadbeing provided via radiomodulation of neural activity.

Behavioral disorders are neurologic and psychiatric conditions that stemfrom defective regulation of certain brain regions. Patients that sufferfrom behavioral disorders often exhibit abnormal neural activity along aparticular neural circuit within the brain. Typically, areas within theneural circuits of the brain of a behavioral disorder patient are eitherover-active or under-active, even though the cells of the tissue appearnormal. This class of pathology contrasts with structural disorders, inwhich there is something morphologically or identifiably and physicallyabnormal with a tissue, such as an injury or a cancerous tumor.Nonetheless, the impact of behavioral disorders, including depression,OCD, addiction, and the like, can be devastating on the lives ofpatients and their families.

In neurology and psychiatry, behavioral disorders are most often treatedwith medications. Unfortunately, these medications can often benon-specific as to where they exert effects within the body. Hence,medications for treatment of behavioral disorders often produceundesirable side effects.

Attempts are being made to treat behavioral disorders by surgicalimplantation of treatment devices. These surgical implants typicallyinclude stimulating electrodes driven by a pacemaker-like pulsegenerator unit. For example, abnormal neuronal activity associated withintractable depression may be inhibited by continuously applyinglocalized electrical current using a process called deep brainstimulation. Unfortunately, deep brain stimulation generally involvesthe invasive placement of electrodes into deep brain structures, alongwith the subcutaneous implantation of an electrical generator withbatteries. Such approaches, however, are expensive, and are generallyaccompanied by risks associated with the surgery, particularly with therisks associated with surgically accessing tissues of the brain forimplantation of the electrodes such as bleeding and infection. Theseapproaches can also suffer from device-related risks, including devicefailure, battery-life limits, and the like.

A variety of both historical and modern techniques seek to treatpatients by effectively killing cells within selected areas of thebrain. Surgical techniques have been developed that intentionally killor ablate specific regions of the brain using a variety of devices andenergy forms. For example, radiation is a widely used method forinducing cell death and effectively destroying tissue within the brain.Radiation is primarily applied to tissues of the brain to treat benignand malignant tumors. The clinical practice of irradiation to produceselective cell death in tumors generally makes use of computerizedsystems that seek to minimize injury to adjacent normal anatomy. Thebiologic effects of radiation are largely ascribed to lethal chromosomalinjury which results in disruption of the normal cell cycle.Non-chromosomal, i.e. epigenetic, pathways of cell injury are alsobelieved to play a role in cellular death under some circumstances.

While inducing necrosis of selected tissues of the brain can be wellworthwhile to halt growth of a malignant tumor or the like, there can besignificant and even debilitating side effects, particularly when thetissues targeted for treatment are associated with higher cognitivefunctions. For example, targeting of apparently healthy tissues of thehyperactive or hypersensitive neural circuits associated withdepression, addiction, OCD, or other behavioral disorders for cellularlylethal doses of radiation might effectively treat the disorder, but maysignificantly degrade cognitive abilities, induce neurologicalside-effects, and impact quality of life of the patient.

In addition to currently recognized neural circuits associated withbehavioral disorders, there is an increasing awareness that abnormalneural activity within the neural circuits of the brain may beassociated with a variety of deleterious behavior patterns. For example,while obesity is not uniformly recognized as a class of psychiatricbehavioral disorder, there is increasing understanding that hyperphagia(excessive appetite and consumption of food) can be associated withexcessive activity in an associated neural circuit. Similar deleteriousbehavior patterns and their associated anatomical structures within thebrain are likely to be identified in the future.

In light of the above, it would generally be desirable to provideimproved medical systems, devices, and methods, particularly fortreatment of behavioral disorders, obesity, and the like. It wouldfurther be desirable if these improved treatment techniques could helpmitigate the debilitating effects of behavioral disorders withoutimposing excessive surgical trauma on the patient, and without having todamage or kill neural tissues throughout an area that might result inloss of significant cognitive, emotional, or physical functionality tothe patient. It would be particularly desirable if these benefits couldbe provided at reasonable costs by modifying existing treatmentinfrastructure and technologies.

BRIEF SUMMARY OF THE INVENTION

The present invention generally provides improved medical systems,devices, and methods. Exemplary embodiments of the invention provideimproved radiosurgical techniques and systems, particularly fortreatment of behavioral disorders (such as depression,Obsessive-Compulsive Disorder (“OCD”), addiction, hyperphagia, and thelike). Related embodiments may be employed for treatment of obesity.Advantageously, radiation can be directed from a radiation sourceoutside the patient toward a target tissue deep within the patient'sbrain using a stereotactic radiosurgical platform, typically withouthaving to impose the surgical trauma associated with accessing deepbrain tissues. The target will often be included in a neural circuitassociated with the behavioral disorder. Rather than applying sufficientradiation to kill the neural tissue within the target, a cellularlysub-lethal dose of the radiation may be applied. Without imposing frankcell death throughout the target, the radiation can mitigate thebehavioral disorder, obesity, or the like, often by modulating the levelof neural activity within the target and in associated tissues.Hypersensitive and/or hyperactive neuronal tissue may be targeted, withthe radiation downwardly modulating hyperactive neuronal activity.Additionally, by down-regulating the activity of a target that normallyexerts negative feedback or a limiting effect on a relevant neuralcircuit, the activity of the circuit may be increased.

In a first aspect, the invention provides a method for treating apsychiatric behavioral disorder or hyperphagia of a patient. Thedisorder or hyperphagia is associated with a level of neuronal activityin a neural circuit within a brain of the patient, and provokesdeleterious volitional behavior by the patient. The method comprisestransmitting a sub-lethal quantity of ionizing radiation from outsidethe patient into a target within the brain of the patient so as to alterthe level of neuronal activity in the neural circuit. By altering theactivity level, the behavioral disorder or hyperphagia is mitigated.

The neural circuit will typically comprise a recognized behavioralneural circuit that is known to be associated with the behavioraldisorder or hyperphagia. A variety of such neural circuits are nowknown, and more are being developed through the use of imagingtechniques which can indicate local neuronal activity levels within thetissues of the brain. Although the overall functioning of the neuralcircuit is often abnormal prior to treatment of a behavioral disorderpatient (for example, with abnormally excessive neuronal activities insome or all of the neural circuit) the neural tissue within the targetwill often be morphologically normal prior to the treatment, so that thetreatment is directed at what may be effectively healthy tissue.Nonetheless, by selecting an appropriate target within the neuralcircuit, and by applying a quantity of radiation that is sufficient todecrease the level of neuronal activity within the targeted neuraltissue (but which is insufficient to generally kill the tissue of thetarget), the level of overall activity of the neural circuit may besafely and effectively decreased without excessively (or evensignificantly) impairing the higher cognitive, emotional, and/orphysical functioning of the patient. Alternatively, where the neuraltissue within the target down-regulates the level of neuronal activitywithin at least a portion of the neural circuit, the radiation maydecrease activity in the neural tissue and lead to an increase in thelevel of neuronal activity within some or all of the neural circuit.

Advantageously, the target may comprise one or more discrete tissuestructure of the brain having anatomical boundaries. The ionizingradiation can be transmitted from a radiation source as a plurality ofradiation beams, and the radiation beams can be planned so thatradiation outside the anatomical boundaries drops off sufficiently toinhibit collateral damage to adjacent neural tissues and preservecognitive function. As the dosage of radiation even within the targetneural tissue is generally cellularly sub-lethal, necrosis outside theanatomical boundaries of the target may be quite limited or evennegligible. The volume of the target will often be quite small, thetarget typically having a volume of less than 0.5 cc, often having avolume of less than 0.125 cc, and in some cases having a volume of lessthan 0.06 cc. To facilitate treatment of these small tissue volumes andminimize collateral tissue damage, some or all of the radiation beamsmay be smaller in cross-section than those used in standardtumor-treatment stereotactic radiosurgery. For example, at least some ofthe radiation beams may be collimated to a beam cross-sectional size ofless than 3 mm.

Before treatment, a medical professional will typically clinicallydetermine that the behavioral disorder falls within an acceptedpsychiatric standard. Such standards may, for example, comprise one ormore of those included within the Diagnostic and Statistical Manual ofMental Disorders, 4th edition (“DSM IV”). The target may be identifiedusing an accepted psychiatric neural circuit associated with thebehavioral disorder of the patient. The target may also be identified,verified, and/or tailored by imaging localized neuronal activity levelsalong the neural circuit of the patient. Hence, for example, once aclinical diagnosis is established and the patient otherwise meets thepatient selection criteria, hyperactivity of a candidate neural circuitknown to be associated with the disorder can verify that the treatmentis appropriate, and the radiation beam trajectories can be planned basedon the anatomical borders of the discrete tissues of the particularpatient. Imaging may also be performed an appropriate tissue responsetime after treatment and to verify that sufficient neuromodulation hasbeen provided, to determine whether a follow-on treatment isappropriate, and/or to plan that follow-on treatment in a fractionatedtreatment regime. It may be advantageous to verify mitigation of thedisorder after more than a month, and often after at least two months,as the changes in the level of neuronal activity may continue for atleast a period of weeks or months after the radiation has been deliveredto the target.

The sub-lethal quantity of radiation may depend at least in part on thevolume of a discrete region of the target tissues. For example, theradiation dose for a single treatment may comprise about 60 Gy when thetarget has a volume of about 0.05 cc (and more specifically when thetarget has a volume of about 0.054 cc). In contrast, the radiation dosemay be significantly less than about 60 Gy when the target has a size ofsignificantly more than about 0.05 cc, and/or more than about 60 Gy whenthe target has a size of significantly less than about 0.05 cc.

A variety of functional disorders and other conditions may be treated bydirecting the radiation to one or more appropriate target(s). Onepreferred treatment may mitigate a behavioral disorder by targetingCg25, though a variety of alternative targets may also be selected. Forexample, depression may be mitigated by targeting a rostral anteriorcingulate (rCg24a); a dorsal anterior cingulate (dCg24); Cg 32; and/or asubgenual cingulate (sCg25 or Cg25). Obsessive-Compulsive Disorder (OCD)may be treated by targeting an internal capsule; BA32; Cg24; a ventralPFC, and/or a dorsal anterior cingulate. Addiction may be treated bytargeting an insula; a genu of the anterior cingulate (BA32); an arcuatenucleus of a medial hypothalamus; an anterior cingulate cortex orBrodmann's area 24; an orbitofrontal cortex; a medial prefrontal cortex;a dorsal anterior cingulate; an anterior limb of an internal capsule; anucleus accumbens; and/or a neural circuit connection between theventral tegmentum and the nucleus accumbens. Hyperphagia and/or obesitymay be mitigated by targeting a lateral nucleus of a hypothalamus and/orbilateral nuclei of the hypothalamus. These and other conditions mayadvantageously be mitigated by transmitting the radiation from outsidethe patient, through a skull and into the brain along beam pathsdirected from varying directions so as to intersect with the target,often without accessing the target and/or the neural circuit.

In another aspect, the invention provides a system for treating apsychiatric behavioral disorder or hyperphagia of a patient. Thedisorder or hyperphagia can be associated with a level of neuronalactivity in a neural circuit within a brain of the patient, and mayprovoke deleterious volitional behavior by the patient. The systemcomprises a source for transmitting ionizing radiation, and a processingsystem coupled to the source. The processing system can be configured toeffect transmission of a plurality of beams of the radiation from thesource into a target within the brain of the patient. The processingsystem can plan the beams so that the radiation within the target has asub-lethal quantity, but is sufficient to alter the level of neuronalactivity in the neural circuit such that the behavioral disorder orhyperphagia is mitigated.

The processing system typically comprises software, with the softwareincluding machine-readable code embodying instructions for planningtransmission of the plurality of beams. The software may, in response toinput command signals received by an input, transmit signals so as toeffect a desired positioning of the radiation beams relative to thetarget, the signals typically comprising drive signals that effectmovement of the source, the patient, or both.

The system may include a neural circuit image capture device coupled tothe processing system. The image capture device may, in use, generateimage data that includes localized neuronal activity levels along theneural circuit in the brain of the patient, the image capture devicecoupled to the processing system. Suitable image capture devices mayinclude a positron emission tomography (PET) system, a single photonemission tomography (SPECT) system, and/or functional magnetic resonanceimaging (fMRI) system.

In some embodiments, the source may comprise a linear accelerator. Theprocessing system can be configured to generate a sequence of beams, anda robot may be coupled to the processing system and support the source.The robot may re-position the source and orient sequential beams towardthe target tissue. One or more registration imaging system may beoriented to obtain patient registration images of the patient duringtreatment. The registration imaging system will typically be coupled tothe processing system, and the processing system may align the beamswith the target (often in three dimensions) in response to registrationsignals from the registration image system. In alternative embodiments,the source may comprise a plurality of cobalt 60 sources distributedgenerally spherically, with an associated plurality of collimatorsoriented generally radially inwardly so that at least some of the beamsare simultaneously directed toward the target.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates components of a robotic stereotacticradiosurgical system and an associated method for applying cellularlysub-lethal ionizing radiation to a target within a brain of a patient soas to treat a behavioral disorder, hyperphagia, obesity, or the like,according to embodiments of the invention;

FIG. 2 is a flow chart schematically illustrating steps included in amethod for treating a behavioral disorder, hyperphagia, or the likeusing the system of FIG. 1 or other radiosurgical systems;

FIG. 3 schematically illustrates a neural circuit associated withdepression, along with candidate tissues suitable for treatmentaccording to embodiments of the invention;

FIGS. 4A and 4B schematically illustrate a patient having target neuraltissues at Cg25 irradiated for treatment of depression according to anembodiment of the invention;

FIG. 5 illustrates a screen print from a planning module included in aprocessing system of the system of FIG. 1 for implementing a treatmentaccording to embodiments of the invention;

FIGS. 6A-6C graphically illustrate exemplary target neural tissues fortreatment of obesity according to embodiments of the invention;

FIGS. 7, 8, and 9 schematically illustrate neural circuits associatedwith hyperphagia or obesity, addiction, and OCD, respectively, alongcandidate target tissues for treatment of each of these behavioraldisorders according to embodiments of the present invention;

FIG. 10 schematically illustrates an alternative stereotacticradiosurgical system for implementing behavioral disorder treatmentsaccording to embodiments of the present invention;

FIG. 11 schematically illustrates radiosurgical neuromodulation of theinsula for treating addiction and/or other behavioral disorders; and

FIG. 12 schematically illustrates representative trajectories to effectradiosurgical neuromodulation of the dorsal anterior cingulate gyrus(Cg24, 32) for treating OCD, depression, and/or other behavioraldisorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention generally provides improved medical systems,devices, and methods. Exemplary embodiments of the invention provideimproved radiosurgical techniques and systems, particularly fortreatment of behavioral disorders, including depression,Obsessive-Compulsive Disorder (“OCD”), and addiction. Treatments arealso provided for additional medical and/or psychiatric conditions,particularly those that are associated with neural activity levels inidentifiable neural circuits of the brain, including hyperphagia andobesity. As treatments described herein may rely on the delivery ofradiation transmitted from a source outside the patient, through theskull and any intervening tissues, and concentrated within the target,these treatments may optionally avoid the surgical trauma associatedwith accessing deep brain tissues. Alternative embodiments could,however, combine non-invasive methodologies described herein withminimally invasive or even traditional open surgical techniques. Whilesome embodiments might employ sufficient radiation to result insignificant necrosis within (or even throughout) the target, exemplaryembodiments will generally limit the radiation to cellularly sub-lethaldosages, so that there will be little or no necrosis. Frank cell deathwill typically be limited or absent, but the radiation will modulate,and typically decrease the overall level of neuronal activity within thetarget. By down-regulating the activity of a target that normally exertsnegative feedback or a limiting effect on another neural tissue, neuralactivity may alternatively be increased.

Advances in brain imaging, especially those involving MRI and PET, arestarting to unravel a spectrum of psychiatric behavioral disorders. Suchimaging modalities have implicated a number of specific anatomic regionsas being involved in some pathologic brain conditions. The alteredimaging characteristics of these regions may allow physicians tovisualize the brain pathology that underlies diseases such as depressionand addiction. In a more specific example, treatment-resistantdepression may particularly benefit from the treatments describedherein. Increased metabolic activity in Brodmann's Area 25 may correlatewell with clinical depression. This anatomical structure may alsointeract with a variety of other anatomical structures having alteredactivity levels in many patients suffering from depression, with theinterrelated tissue structures generally defining an abnormallyfunctioning neural circuit model. Using these imaging techniques and/orthe neural circuits that have been identified for specific behavioraldisorders, the effects of therapy for those behavioral disorders may bemonitored by means of MRI and PET.

The neural tissues targeted for the radiation treatments describedherein will often be included within an abnormally functioninghigh-level neural circuit of the patient's brain. In some cases, thetarget may not be in the neural circuit itself, but may functionallyinteract with a tissue included in the neural circuit, with activity inthe target effectively up-regulating activity A variety of neuralcircuits are known to be associated with individual behavioraldisorders. Exemplary neural circuits associated with depression,Obsessive-Compulsive Disorder (“OCD”), addiction, and obesity aredescribed hereinbelow, and these exemplary circuits may be used toidentify appropriate tissues to target for patient having thesedisorders or conditions. The invention is not, however, limited to thespecific behavioral disorders and/or neural circuits provided herein, asadditional and more refined neural circuits are (and will continue tobe) developed.

In some embodiments, the overall neural circuits associated with thedisorder may also, at least in part, be determined, refined, and/orverified by appropriate imaging of a specific candidate patientsuffering from a disorder. In some embodiments, hyperactivity along aneural circuit may be seen in a patient having an acute or ongoingepisode by imaging the neural tissues with imaging modalities thatindicate localized neuronal activity levels. For example, by stimulatingan addict with appropriate drug paraphernalia images or the like, theneuronal activity may be imaged and measured along an addiction neuralcircuit to verify that particular neural circuit model is applicable tothe patient, to verify that a candidate target neural tissue becomeshyperactive during the episode, and to tailor the target shape to theanatomical boundaries of the patient's brain physiology. Treatments maybe fractionated, with follow-up clinical diagnosis and/or imaging afterat least one treatment to determine whether additional modulation of thesame target is appropriate, to select additional targets, or todetermine that treatments can be suspended or terminated. More directly,treatments may be repeated if inadequate clinical response has beenobtained.

Radiosurgery is an established method for using intense, highly accurateirradiation to non-invasively ablate (killing or otherwise destroying)abnormal tissue within the body, for example, brain tumors. Examples ofradiosurgical platforms include the Cyberknife (Accuray, Inc., SantaClara, Calif.), the Gamma Knife (Elekta, Stockholm Sweden), and theTrilogy System (Varian, Palo Alto, Calif.). These or other commerciallyavailable radiosurgery systems may be modified to take advantage of theinventions described herein, or specialized radiosurgical systems fortreatment of behavioral disorders may be employed.

The present invention often applies radiosurgical platforms forneuromodulation rather than ablation. Radiomodulation (“RM”) (alsoreferred to herein as radiosurgical neuromodulation) encompasses the useof non-necrosing stereotactic radiosurgery for the down-regulation ofselected neural structures. Advantageously, small and strategicallyimportant neuronal regions may be treated with dosages of radiation thatare sufficiently low to leave their tissues alive and functional, butare sufficiently high to make them less reactive, and less able totrigger action potentials, i.e. precipitate deep-brain neuromodulationclinical response. A variety of data may be applied to identifyappropriate dosages to alter brain function without frank cell death.Irradiation of the entire brain of patients produces long term cognitivedecline without producing clear evidence of tissue necrosis, and mayproduce other undesired emotional and physically-manifested neurologicalsymptoms. Decreased neuronal excitability within hippocampal slices ofpig brain has been revealed by in vitro evidence. Moreover, treatment oftrigeminal neuralgia with radiosurgery has been found to provide symptomrelief that does not correlate temporally with facial numbness. In fact,treatment of more than 100 patients with refractory trigeminal neuralgiahas shown that the complete remission of pain occurs in a setting ofessentially normal facial sensation. Dose application rates may alterthe total dosages to achieve a desired result. At dose rates of 20 Gyper minute, synaptic damage (lessened ability to transmit excitation toanother neuron) may occur when a 50 Gy total dose had accumulated. Dosesof 75 Gy and greater may provide both synaptic and postsynaptic damage(lessened ability of a downstream neuron to produce an actionpotential). At slower delivery rates of about 5 Gy/min, however, a totaldose of 100 Gy or more may be applied to induce synaptic impairment,while post-synaptic impairment may not be dose-rate dependent.Appropriate dosages may also vary with the inverse of a volume or sizeof the target. One exemplary treatment of a target volume of about 3 mmby about 3 mm by about 6 mm (about 0.054 cc) will employ a dosage ofabout 60 Gy to achieve RM; significantly larger target volumes mayemploy lower dosages; while smaller target volumes may employsignificantly higher dosages.

While many embodiments do not rely on any particular mechanism or theoryof operation, ionizing radiation may cause an inhibitory effect uponvoltage-sensitive sodium channels in the brain. This may results in astate in which affected neurons remain chronically in a hyperpolarizedstate, which is resistant to depolarization. Radiation may also resultin the thickening of blood vessel walls and narrowing of lumens, to thepoint of frank destruction of the microvasculature, leading to reducedblood delivery capacity within an irradiated area. These effects may beprogressive over time after radiation exposure, reaching a steady state.Additionally, the blood-brain barrier may be disrupted by ionizingradiation, allowing release of neuromodulatory substances such asneurotensin, histamine and serotonin. Hence, moderate-dose radiation mayalter neuronal and synaptic activity through mechanisms that change thefunctional characteristics of individual cells without killing thosecells. By physiologically altering, but not destroying, discrete neuralcircuits, brain activity can be modulated.

Referring now to FIG. 1, an exemplary stereotactic radiosurgery system10 for treatment of a behavioral disorder or hyperphagia of a patient Pdirects ionizing radiation 12 to a target T in a brain B of the patient.System 10 includes a linear accelerator 14 supported by a 6 degree offreedom robot 16, which allows the linear accelerator to be moved aroundthe patient, so that radiation 12 can be directed to target T as asequential series of beams that pass through different intermediatetissues from a variety of different orientations, thereby limiting theamount of radiation outside the target.

System 10 also includes a processing system 18 that is coupled to linearaccelerator 14 to control transmission of radiation 12. Processingsystem 18 is also coupled to robot 16, and optionally to an automatedpatient support 20 to reposition radiation 12 relative to the patient Pand target T. Processing system 18 may also be coupled to one or moreimaging system(s) used for planning of the treatments, to imagingsystems 22 a and 22 b used to register radiation beam 12 with target Tin three dimensions and/or track patient movements during treatment.Registration imaging systems, the linear accelerator, the robot, and thepatient support may be the same as or modified from commerciallyavailable robotic radiosurgical systems, including the CyberKniferadiosurgical system. Additional or modified imaging structures andsystems will often be coupled to processing system 18 so as to provideinput for planning the treatment and the like, such as a neural activityimaging system 24.

To facilitate treatment of the relatively small volume discreteanatomical structures of the neural circuits, system 10 will typicallyinclude a collimator 32 which selectably narrows beam 12 to beamcross-sectional sizes of 3 mm or smaller, and in some embodiments to across-sectional size of 5 mm or smaller.

Processing system 18 may include some or all of the components of acommercially available computer system. Processing system 18 will, forexample, typically includes at least one hardware processor circuit,which may communicate with a number of peripheral devices via a bussubsystem. These peripheral devices may include a memory system, and thememory will typically include a tangible storage media 26 embodyingmachine (i.e., computer) readable instructions for performing methods(including those described herein) and/or data. The memory may comprisea random access memory (RAM), a read only memory (ROM), a persistent(non-volatile) storage such as a hard disk drive, a floppy disk drivealong with associated removable media, a Compact Digital Read OnlyMemory (CD-ROM) drive, an optical drive, DVD, CD-R, CD-RW, solid-stateremovable memory, and/or other removable media cartridges or disksincluding flash RAM.

In some embodiments, processing system 18 will comprise a proprietarystructure, and will likely include a plurality of discrete processingcircuits, with separation structures of the processing system beingprimarily used for planning treatments, analyzing neural images,controlling movement of robotic components of system 10, and the like.Alternatively, simpler systems might employ a single processor chiprunning a monolithic computer program and packaged with single input 28and display 30. Hence, a wide variety of centralized or distributed dataprocessing hardware and software architectures may be implemented, andthe functionality described herein may be implemented in a variety ofsoftware and/or hardware modules distributed in different dataprocessing structures and locations. Exemplary embodiments of theprocessing system 18 of system 10 may be provided by input to andmodifications of the data processing and signal transmission systems ofcommercially available radiosurgery systems such as the CyberKnife™robotic stereotactic system from Accuray, Inc.

Referring now to FIG. 2, an exemplary method 100 for treatment of abehavioral disorder, hyperphagia, obesity, and/or the like will oftenbegin with the selection of an appropriate candidate patient. Such apatient will typically have a neuropsychiatric brain disorder for whichthere is reason to believe that one or more specific regions of thebrain are overactive or hypermetabolic. This diagnosis may beaccomplished via clinical judgment 102, and/or may be accomplished withthe aid of functional brain imaging 104. In clinically diagnosing abehavioral disorder, a medical professional will typically clinicallydetermine that the behavioral disorder falls within an acceptedpsychiatric standard. Such standards may, for example, comprise one ormore of those included within the Diagnostic and Statistical Manual ofMental Disorders, 4th edition (“DSM IV”). Suitable imaging techniquesfor behavioral disorder diagnosis will generally indicate localizedneuronal activity levels, with exemplary imaging systems optionallycomprising positron emission tomography (PET), single photon emissiontomography (SPECT) or functional magnetic resonance imaging (fMRI).Imaging of the patient's head preferably involves acquiring both a highresolution MRI scan of the patient's brain and a thin section CT scan ofthe same region.

Neural circuits associated with the behavioral disorder may beidentified 106 before or after imaging 104. Suitable neural circuits maycomprise neural circuit models indicating functionally related tissuesthat have abnormal activity levels, as determined from a population ofpatients having the associated behavioral disorder. Exemplary neuralcircuits are shown in FIG. 3 (depression), FIG. 7 (hyperphagia and/orobesity), FIG. 8 (addiction), and FIG. 9 (OCD). One or more candidateanatomical target corresponding with the behavior is identified 108 inthe context of the surrounding anatomy using the identified neuralcircuit 106 and/or the data from imaging 104. The imaging data may beused to verify, tailor, and or modify the candidate target 110. Forexample, the depression circuit 130 of FIG. 3 may be identified inresponse to a clinical diagnosis of depression within the DSM IVcriteria, and imaging of the patient's brain may verify hyperactivity ofCg25, indicating this is a suitable candidate target. The anatomicalboundaries of the target tissue (Cg25 in our example) for the patientmay also be identified using the imaging data.

In step 112, a cellularly sublethal radiation dose is selected. Unliketraditional ablative radiosurgery dosing, the goal in many embodimentsof the present invention is explicitly to not destroy the brain tissueeffected, but rather to simply lower its reactivity, metabolic activity,and/or spontaneous firing rate. For example, a dose of 60 Gy may beprescribed to the target volume, with a maximum dose at any point of 75Gy during one treatment stage. The selected dose should be sublethal toneurons, but effective in lowering their activity.

In step 114, preferably using a fused data set of each patient, theradiation treatment is planned. The Cyberknife™ treatment planninginterface (or a modified version thereof), may, for example, be used todelineate, an approximately 5 mm³ target volume within the subgenualcingulute. Referring to FIGS. 2 and 5, a screen print 128 of theCyberknife™ treatment planning interface shows how the systemfacilitates planning of beam trajectories. The planning system shouldalgorithmically seeks to achieve a steep dose gradient in theimmediately surrounding brain. The radiosurgical platform will thencompute a set of beam delivery trajectories in order to achieve theprescribed dose. These planning steps will often be performed on aseparate computer circuit than that used to control the robot andactivate the radiation source, with these separate data processingstructures herein being referred to as elements of processing system 18.

The completed plan will be loaded into the treatment circuitry of theradiosurgical platform, for example a Cyberknife system, and theradiomodulation procedure will be performed 116. In the CyberKnifetreatment room the patient is positioned supine on the procedure tablewhile immobilized in a custom molded mask. The patient will beregistered with respect to the spatial coordinates of the Cyberknifesystem, using an x-ray camera/CT matching system. Once properregistration has been confirmed, radiation delivery proceeds inaccordance with the treatment plan described above, for example, at 60Gy (Dmax 75 Gy) is delivered to the Cg25 target. Because radiationeffects manifest a significant time 118 after surgery, a tissue responsetime of at least a plurality of weeks will pass before evaluation of theeffects of treatment 116 is complete. Tissue response times will oftenbe at least a month, more typically being a plurality of months, and inexemplary embodiments, may be about 90 days, so that clinical evaluation120 of the treatment occurs approximately 90 days following treatment.

In clinical evaluation of the patient 120, the patient is re-evaluated,and may have additional neuroimaging (step 104, repeated) done. Clinicalevaluation and/or imaging endpoints may determine whether a second stageof RM treatment is warranted. Criteria for recommending an additionstage of RM may include insufficient clinical response to previous RMstages, absence of sufficient metabolic decrease (for example in Cg25),and/or absence of significant impairment of surrounding brainstructures.

Referring now to FIG. 3, exemplary target neural tissues included in aneural circuit 130 associated with depression are identified using aschematic radiation source 210 and associated radiation beam 212directed to the target tissues. The solid small arrows shown on thisneural circuit diagram schematically illustrate reciprocalcorticolimbic, limbic-paralimbic, and cingulate-cingulate connections.The dotted arrows illustrate cortico-striatial-thalamic pathways. Thedashed arrows show potential action in which remission to depressionoccurs when there is inhibition of the overactive ventral regions andactivation of the previously hypofunctioning dorsal areas. This effectmay be facilitated by antidepressant action in the brain stem,hippocampus, and posterior cingulate gyrus. Candidate target tissues ofneural circuit 130, as shown in FIG. 3, may include a dorsal anteriorcingulate cortex dCg24; a rostral anterior cingulate cortex rCg24a;Cg32; and/or a subgenual cingulate cortex sCg25 (sometimes referred toherein as Brodmann's Area 25, a subgenual cingulate, or Cg25). Anexemplary treatment for depression will, for example, comprise targetingof Cg25. Other tissues included in neural circuit 130 include dorsalprefrontal cortex or dorsolateral prefrontal cortex dFr9/46;parahippocampus-medial temporal ph-mT; premotor frontal cortex pmF6;pariental cortex or posterior insula Par40/pins; striatum-globuspallidus St-gp; thalamus thal; pons; hypothalamus hth; anterior insulaA-Ins; hippocampus hc; parahippocampus or medial temporal lobe Ph-mT;and posterior cingulate cortex pCg23/31. Additional informationregarding related neural circuits is available from a number of sources,including the publications of Helen Mayberg and other others.

Referring now to FIGS. 4A and 4B, patient's head 200 is illustrated incross-section along plane 201. Within brain 202, subgenual cingulatetarget 225 (Cg25) is visible. Radiation source 210 is schematicallyillustrated delivering a beam along trajectory 211, and will also beused (by robotically moving the source) to direct radiation alongtrajectory 212, and trajectory 214, all of which intersect at target225. The total dose of radiation to be received by target 225 downwardlymodulates target 225 reactivity, metabolic rate, and/or spontaneousfiring rate, but does not tend to ablate or destroy the tissue (Cg25)within the target.

Referring to FIG. 5, a screen shot 128 of an interface for planning of aRN treatment for mitigation of a behavioral disorder per the system userinput is shown. Screen shot 128 may also indicate gradients of radiationto which adjacent neural tissues are subjected, as well as thetrajectories of radiation beams generated by the software. Tissues whichare desired to have particularly limited radiation may also beidentified by the input from the system user, so that the systemcalculates appropriate trajectories to limit collateral tissue damage ofsensitive structures.

FIGS. 6A-6C and 7 illustrate a process by which obesity and/orhyperphagia may be treated and a neural circuit associated with obesity.In the exemplary method obesity and excessive eating disorders may betreated by radiomodulation of the lateral nuclei of the hypothalamus.The nuclei of the lateral hypothalamus, which comprises the lateralhypothalamic area, is a portion of the brain which creates the sensationof hunger. For example, when the blood sugar level declines, thismessage is relayed to the lateral hypothalamic area, which then causes asensation of hunger to be felt. This feeling will continue untiladequate glucose in the blood signals the ventromedial nuclei of thehypothalamus, which creates a sensation of satiety. Damage to thelateral hypothalamic area can lead to reduced food intake.High-frequency deep brain stimulation, which typically has an inhibitoryeffect upon stimulated structures, leads to a similar reduced appetitestate. In this embodiment, obesity treatment may instead be providedusing radiomodulation to the lateral nuclei of the hypothalamus,typically on each side of the brain.

In FIG. 6A, patient 400 is treated with radiation beams 415(representative example of other radiation beams, also illustrated asdotted lines with arrows). These radiation beams may come from anynumber of sources known in the art, including the Cyberknife (Accuray,Inc., Santa Clara, Calif.), or Gamma Knife 405 (Elekta, Stockholm,Sweden). Additionally, ion beam particle therapy may be utilized forthis and the other treatments described herein (IBA, Belgium). Beams 420are shown aimed at right lateral hypothalamic area 415, which lieswithin the dashed lines bounding region 410. FIGS. 6B and 6C illustratesan intermediate 410 view and a closeup view 411 of the region,respectively. The target here includes both the right lateralhypothalamic area 450, and left lateral hypothalamic nucleus 460, bothnuclei shaded in the diagrams for illustrative purposes. The desiredradiomodulation effects may be achieved, for example, by delivering adose such as 60 Grey of radiation to each of those targets, withsubsequent fractions delivered as needed. A steep gradient 440 adjacentthe anatomical boundaries 445 of the target neural tissues limitscollateral damage to adjacent tissues.

FIGS. 7-9 schematically illustrate neural circuits associated withhyperphagia or obesity, addiction, and OCD, respectively. Firstaddressing FIG. 7, exemplary target neural tissues included in a neuralcircuit 170 associated with hunger and obesity are again identifiedusing a schematic radiation source 210 and associated radiation beam 212directed to the target tissues. The solid small arrows shown on thisneural circuit diagram schematically illustrate neural connections.Candidate target tissues of neural circuit 170, as shown in FIG. 7, mayinclude the lateral hypothalamic area, the portion of the brain whichcreates the sensation of hunger. Other tissues included in neuralcircuit 170 include the frontal cortex, cingulate, basal ganglia, thethalamaus, the paraventricular nucleus of the thalamus, other thalamicnuclei, the hypothalamus, the ventromedial nucleus of the hypothalamus,the arcuate nucleus of the hypothalamus, the brainstem, the reticularformation of the brain stem, the intermediolateral column of thebrainstem, the parabrachial nucleus of the brainstem, the solidatrytract and nucleus of the brainstem, and other limbic structuresincluding the hippocampus, the parahippocampal gyrus, the uncus and theamygdala.

Referring now to FIG. 8, exemplary target neural tissues included in aneural circuit 180 associated with addiction are again identified usinga schematic radiation source 210 and associated radiation beam 212directed to the target tissues. The solid small arrows shown on thisneural circuit diagram schematically illustrate neural connections.Candidate target tissues of neural circuit 180, as shown in FIG. 8, mayinclude the prefrontal cortex, orbitofrontal cortex, medial prefrontalcortex, the dorsal anterior cingulate, the insula, the neural connectionbetween the insula and the cingulate, the anterior limb of the internalcapsule, the nucleus accumbens, the neural connection between thenucleus accumbens and the ventral tegmentum, the neural connectionbetween the nucleus accumbens and the substantia nigra pars reticularisand the neural connection between the nucleus accumbens and the globuspallidus. Other tissues included in neural circuit 180 include theposterior cingulate, the subgenual anterior cingulate, the amygdala, thethalamus, the medial nuclei of the thalamus, the anterior nuclei of thethalamus, the cerebellum, the pons, the medulla, the ventral tegmentumand the basal ganglia, including the caudate, the putamen, the globuspallidus and the substantia nigra pars reticularis.

Referring now to FIG. 9, exemplary target neural tissues included in aneural circuit 190 with Obsessive-Compulsive Disorder (OCD) are onceagain identified using a schematic radiation source 210 and associatedradiation beam 212 directed to the target tissues. The solid smallarrows shown on this neural circuit diagram schematically illustrateknown neural connections. The dashed arrows shown on this neural circuitdiagram schematically illustrate hypothesized connections. Candidatetarget tissues of neural circuit 190, as shown in FIG. 9, may includethe ventral prefrontal cortex (PFC), the dorsal anterior cingulate andthe anterior limb of the internal capsule (Ant. Limb of InternalCapsule). Other tissues included in neural circuit 190 include thefrontal cortex, the parietal cortex, the motor cortex, Brodmann area 39,the cingulate, the posterior cingulate, the subgenual anteriorcingulate, the amygdala, the basal ganglia, the caudate of the basalganglia, the putamen of the basal ganglia, the globus pallidus of thebasal ganglia, the thalamus, the medial nuclei of the thalamus, theanterior nuclei of the thalamus, the cerebellum, the pons and medulla.

Referring now to FIG. 10, radiosurgical systems having quite differentstructures may be employed in the treatments of behavioral disordersdescribed herein. Here, a radiosurgical system 470 includes a radiationsource having a spherical array of discrete cobalt 60 sources 472, witheach source having an associated collimator 474 so as to direct a beamof radiation radially inwardly. Shielding 476 and doors 478 limitrelease of radiation, and an automated positioning system 480 helpsposition the target tissues at the center of the radiation beamtrajectories. A helmet 482 is rigidly affixed to the head of thepatient, and may include at least a portion of the collimators. Thehelmet is mounted to helmet supports 484, and the helmet and patient (ona movable treatment surface 486) are translated into alignment with theradiation source. Hence, at least some of the radiation beams may bedelivered simultaneously, with the alignment and dosages again beingdetermined by processing system 18.

A wide variety of behavioral disorders and conditions may be treatedusing the systems and method described herein. FIG. 11 illustrates amethod for treatment of addiction (for example nicotine addiction) byradiomodulation (in this exemplary embodiment by irradiation of theinsula). Addiction is associated with a variety of brain functions,including reward and expectation, and the driving neuroanatomic sourcesof addiction may vary between individuals. A patient with brain 510 hasa region known as the insula. After the specific site of metabolicabnormality within the insula has been localized (for example bycued-state PET or fMRI) that locus, insula target 520 may be treated.Representative sample radiation beams 530 are shown converging uponinsula target 520. For example the desired radiomodulation effects maybe achieved by delivering a dose such as 60 Grey of radiation to each ofthose targets, with subsequent fractions delivered as needed.

Alternative embodiments of radiomodulation methods for treatment ofaddiction may also be provided. For example, the nucleus accumbens andseptum may be used to decrease drug craving in the context of addiction.In an alternative embodiment, radiomodulation of hypermetabolic activityobserved at the genu of the anterior cingulate (BA32) can be used todecrease drug craving. Alternatively, radiomodulation of the arcuatenucleus of the medial hypothalamus which contain peptide products ofpro-opiomelanocortin (POMC) and cocaine-and-amphetamine-regulatingtranscript (CART) can also be used to decrease drug addiction behavior.

Additionally, addiction may be effectively treated by radiomodulation ofthe anterior cingulate cortex, also known as Brodmann's area 24. Thissame treatment is also effective for obsessive compulsive disorder. FIG.12 illustrates the radiomodulation of the anterior cingulate cortex.Brain 610 includes anterior cingulate cortex target 630. Representativesample radiation beams 620 are shown converging upon anterior cingulatecortex target 630. The desired radiomodulation effects may be achieved,for example, by delivering a dose such as 60 Grey of radiation to eachof those targets, with subsequent fractions delivered as needed.

Obsessive-Compulsive Disorder (OCD) may also be treated byradiomodulation treatments. Destructive lesions to the anterior capsule,and analogous DBS to that region are established means of treatingsevere, intractable OCD. Such approaches may be emulated (with lessdamage to the tissue, and potentially, less damage to higher cognitivefunctions) using radiomodulation to the anterior limb of the internalcapsule, or alternatively, to regions such as BA32 and Cg24 (which showmetabolic decrease as OCD remits). The desired radiomodulation effectsmay be achieved, for example, by delivering a dose such as 60 Grey ofradiation to each of those targets, with subsequent fractions deliveredas needed.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, those of skill in theart will recognize that a variety of modification, adaptations, andchanges may be employed. Hence, the scope of the present inventionshould be limited solely by the appending claims.

1. A method of treating a psychiatric disorder or a neurologicaldisorder of a patient, the psychiatric disorder or the neurologicaldisorder of the patient associated with a level of neuronal activity ina neural circuit within a brain of the patient, the method comprising:transmitting a cellularly sub-lethal quantity of ionizing radiation fromoutside the patient into a target comprising at least a portion of theamygdala within the brain of the patient so as to alter the level ofneuronal activity in the neural circuit such that the psychiatricdisorder or the neurological disorder is mitigated, wherein theradiation is transmitted from a radiation source machine outside thepatient, through a skull of the patient and into the brain of thepatient along a plurality of beam paths directed from varying directionsso as to intersect with the target.
 2. The method of claim 1, whereinthe psychiatric disorder or the neurological disorder isobsessive-compulsive disorder.
 3. The method of claim 1, wherein thepsychiatric disorder or the neurological disorder is associated withaddiction.
 4. The method of claim 1, wherein the psychiatric disorder orthe neurological disorder is associated with anxiety.
 5. The method ofclaim 1, wherein the psychiatric disorder or the neurological disorderis associated with depression.
 6. The method of claim 1, wherein theionizing radiation is transmitted with a cross-sectional size of lessthan 5 mm.
 7. The method of claim 6, wherein the ionizing radiation istransmitted with a cross-sectional size of less than 3 mm.
 8. The methodof claim 1, wherein the target is morphologically normal tissue.
 9. Themethod of claim 1, wherein the target for the ionizing radiationcomprising at least the portion of the amygdala has a volume of lessthan 0.5 cc.
 10. The method of claim 1, wherein an activity of theamygdala is decreased by the transmission of the quantity of ionizingradiation.
 11. A system for treating a psychiatric disorder or aneurological disorder of a patient, the psychiatric disorder or theneurological disorder of the patient associated with a level of neuronalactivity in a neural circuit within a brain of the patient, the systemcomprising: a source for transmitting ionizing radiation; and aprocessing system coupled to the source, the processing systemconfigured to effect transmission of a plurality of beams of theradiation from the source into a target comprising at least a portion ofthe amygdala within the brain of the patient so that the radiationwithin the target is a sub-lethal quantity and is sufficient to alterthe level of neuronal activity in the neural circuit such that thepsychiatric disorder or the neurological disorder is mitigated.
 12. Thesystem of claim 11, wherein the psychiatric disorder or the neurologicaldisorder is obsessive-compulsive disorder.
 13. The system of claim 11,wherein the psychiatric disorder or the neurological disorder isassociated with addiction.
 14. The system of claim 11, wherein thepsychiatric disorder or the neurological disorder is associated withanxiety.
 15. The system of claim 11, wherein the psychiatric disorder orthe neurological disorder is associated with depression.
 16. The systemof claim 11, wherein the ionizing radiation is transmitted with across-sectional size of less than 5 mm.
 17. The system of claim 16,wherein the ionizing radiation is transmitted with a cross-sectionalsize of less than 3 mm.
 18. The system of claim 11, wherein the targetis morphologically normal tissue.
 19. The system of claim 11, whereinthe target for the ionizing radiation has a volume of less than 0.5 cc.20. The system of claim 11, wherein the ionizing radiation is configuredto decrease an activity of the amygdala.